Finding vaccine-induced immune response biomarkers that predict vaccine-protection against HIV-1 and other significant pathogen infection, and understanding their role as mechanisms of protection, is an essential part of the vaccine research. We distinguish between three stages in the study of immune correlates. The first stage deals with measurement of immune response and may involve design of experiments. The second stage performs preprocessing of immune response biomarkers obtained in the first stage to form composite biomarkers. The third stage examines the association between clinical outcome and immune response biomarkers. We will develop novel statistical methods for each stage in each of the three aims in order to reduce noise in immune response measurements (Aim 1 & 2), reduce multitesting burden (Aim 2), improve estimation of immune response thresholds required for protection (Aim 3), and improve the power for identifying nonlinear immune correlates (Aim 3). In addition, we will develop statistical methods for HIV-1 envelope protein sequence analysis (subaim 3(iii)) to gain insight into the mechanisms of immune correlates function, as well as the mechanisms of HIV-1 recognition by broadly neutralizing antibodies.